Abstract
Fms-like tyrosine kinase 3 (FLT3) with internal tandem duplications (ITD) is a major oncoprotein in acute myeloid leukemia (AML), and confers an unfavorable prognosis. Interference with FLT3ITD signaling is therefore pursued as a promising therapeutic strategy. In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has anti-proliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines. This effect is mediated in part by arresting FLT3ITD in an underglycosylated state and thereby attenuating FLT3ITD-driven AKT and ERK signaling. In addition, tunicamycin caused pronounced endoplasmatic reticulum stress and apoptosis through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activation of the gene encoding CCAAT-enhancer-binding protein homologous protein (CHOP). PERK inhibition with a small molecule attenuated CHOP induction and partially rescued cells from apoptosis. Combination of tunicamycin with potent FLT3ITD kinase inhibitors caused synergistic cell killing, which was highly selective for cell lines and primary AML cells expressing FLT3ITD. Although tunicamycin is currently not a clinically applicable drug, we propose that mild inhibition of N-glycosylation may have therapeutic potential in combination with FLT3 kinase inhibitors for FLT3ITD-positive AML.
Highlights
Acute myeloid leukemia (AML) is a frequent form of leukemia in adults
In this study we show that abrogation of FLT3ITD glycoprotein maturation using low doses of the N-glycosylation inhibitor tunicamycin has antiproliferative and pro-apoptotic effects on FLT3ITD-expressing human and murine cell lines
The main finding of this study is the synergistic enhancement of cytotoxic effects of FLT3ITD kinase inhibition with low doses of tunicamycin in acute myeloid leukemia (AML) cell lines and primary, FLT3ITD-positive AML cells
Summary
Acute myeloid leukemia (AML) is a frequent form of leukemia in adults. Despite significant improvements in the past, treatment possibilities are still limited and prognosis especially for elderly patients is unfavorable [1, 2]. Intracellular FLT3ITD, e.g. still bound to the endoplasmic reticulum (ER) efficiently activates STAT5, a hallmark of cell www.impactjournals.com/oncotarget transformation, whereas surface-bound FLT3ITD activates AKT and ERK signaling [7, 8]. Drugs which further impair glycosylation of FLT3ITD were found being anti-proliferative for FLT3ITD-positive AML cells One of these compounds is fluvastatin, a clinically applied inhibitor of mevalonate synthesis, which apart from blocking cholesterol synthesis inhibits N-glycosylation by depleting cells of dolicholphosphate [9]. In FLT3ITD-harboring cells, ER-stress through activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP), as well as inhibition of FLT3ITD glycosylation and thereby attenuation of AKT and ERK activation contributed to growth arrest and apoptosis induction. In combination with FLT3 kinase inhibitors, tunicamycin exhibited a strong and specific synergy in killing of FLT3ITD-expressing cell lines and primary AML cells
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